Heat shock protein-related diagnostic signature and molecular subtypes in ankylosing spondylitis: new pathogenesis insights.

Heat shock proteins (HSP) have been associated with a range of persistent inflammatory disorders; however, little research has been conducted on the involvement of HSP in the development of ankylosing spondylitis (AS). The research aims to identify a diagnostic signature based on HSP-related genes and determine the molecular subtypes of AS. We gathered the transcriptional data of patients with AS from the GSE73754 dataset and conducted a literature search for HSP-related genes (HRGs). The logistic regression model was utilized for the identification of hub HRGs associated with AS. Subsequently, these HRGs were employed in the construction of a nomogram prediction model. We employed a consensus clustering approach to identify novel molecular subgroups. Subsequently, we conducted functional analyses, encompassing GO, KEGG, and GSEA, to elucidate the underlying mechanisms between these subgroups. To assess the immunological landscape, we employed the xCell algorithm. Through logistic regression analysis, the four core HRGs (CCT2, HSPA6, DNAJB14, and DNAJC5) were confirmed as potential biomarkers for AS. Subsequent stratification revealed two distinct molecular phenotypes, designated as Cluster 1 and Cluster 2. Notably, Cluster 2 was characterized by the upregulation of pathways pertinent to immune response and inflammation. Our research suggests that the CCT2, HSPA6, DNAJB14, and DNAJC5 exhibit potential as effective blood-based diagnostic biomarkers for AS. These findings contribute to a deeper comprehension of the underlying mechanisms involved in the development of AS and offer potential targets for personalized therapeutic interventions.

Implementation of early prophylaxis for deep-vein thrombosis in intracerebral hemorrhage patients: an observational study from the Chinese Stroke Center Alliance.

BACKGROUND: There is substantial evidence to support the use of several methods for preventing deep-vein thrombosis (DVT) following intracerebral hemorrhage (ICH). However, the extent to which these measures are implemented in clinical practice and the factors influencing patients' receipt of preventive measures remain unclear. Therefore, we aimed to evaluate the rate of the early implementation of DVT prophylaxis and the factors associated with its success in patients with ICH. METHODS: This study enrolled 49,950 patients with spontaneous ICH from the Chinese Stroke Center Alliance (CSCA) between August 2015 and July 2019. Early DVT prophylaxis implementation was defined as an intervention occurring within 48 h after admission. Univariate and multivariate logistic regression analyses were conducted to identify the rate and factors associated with the implementation of early prophylaxis for DVT in patients with ICH. RESULTS: Among the 49,950 ICH patients, the rate of early DVT prophylaxis implementation was 49.9%, the rate of early mobilization implementation was 29.49%, and that of pharmacological prophylaxis was 2.02%. Factors associated with an increased likelihood of early DVT prophylaxis being administered in the multivariable model included receiving early rehabilitation therapy (odds ratio [OR], 2.531); admission to stroke unit (OR 2.231); admission to intensive care unit (OR 1.975); being located in central (OR 1.879) or eastern regions (OR 1.529); having a history of chronic obstructive pulmonary disease (OR 1.292), ischemic stroke (OR 1.245), coronary heart disease or myocardial infarction (OR 1.2); taking antihypertensive drugs (OR 1.136); and having a higher Glasgow Coma Scale (GCS) score (OR 1.045). Conversely, being male (OR 0.936), being hospitalized in tertiary hospitals (OR 0.778), and having a previous intracranial hemorrhage (OR 0.733) were associated with a lower likelihood of early DVT prophylaxis being administered in patients with ICH. CONCLUSIONS: The implementation rate of early DVT prophylaxis among Chinese patients with ICH was subpar, with pharmacological prophylaxis showing the lowest prevalence. Various controllable factors exerted an impact on the implementation of early DVT prophylaxis in this population.

METTL1 facilitates ameloblastoma invasive growth via MAPK signaling pathway.

OBJECTIVES: Ameloblastoma (AM), a common odontogenic epithelial tumor, exhibits aggressive growth due to incomplete encapsulation within the jawbone. Postoperative recurrence is a significant concern, closely associated with its invasive nature. We investigate the role of tRNA N-7 methylguanosine (m7G) modification mediated by Methyltransferase-like 1 (METTL1) in AM's invasive growth and prognosis. MATERIALS AND METHODS: METTL1 expression was analyzed in diverse cell lines and clinical AM tissues. Its association with postoperative AM recurrence was examined. Functional experiments included METTL1 gene silencing using shRNA in hTERT-AM cells, assessing cell proliferation, migration, and invasion. Xenograft tumor model was constructed to investigate tumor growth. Molecular mechanisms behind METTL1's role in AM invasiveness were elucidated using Ribosome nascent-chain complex-bound mRNA sequencing (RNC-seq) and experimental analysis. RESULTS: High METTL1 expression was significantly associated with postoperative recurrence in AM. The inhibition of AM development following METTL1 knockdown has been corroborated by experiments conducted both in vitro and in vivo. Analysis of RNC-seq data revealed that downregulated genes were predominantly enriched in the mitogen-activated protein kinase (MAPK) signaling pathway, suggesting that METTL1 may promote AM's invasive growth through the MAPK signaling pathway. CONCLUSION: Our study elucidates the functional role of METTL1 in AM's invasive development and prognosis. High METTL1 expression is linked to postoperative recurrence, and METTL1 appears to promote AM invasiveness through the MAPK signaling pathway. These findings contribute to a better understanding of AM pathogenesis and may guide future therapeutic strategies.

Comparison of complications and indwelling time of midline catheter at different tip locations: A systematic review and meta-analysis.

This review was performed to determine whether different tip locations of a midline catheter can cause differences in the incidence of complications and the catheter indwelling time. PubMed, Embase, Web of Science, the Cochrane Library, Cumulative Index to Nursing and Allied Health Literature (CINAHL), China National Knowledge Infrastructure (CNKI), and Wanfang were systematically searched. RevMan 5.3 software was used for the meta-analysis. Heterogeneity was evaluated, and the mean differences or odds ratios with 95% confidence intervals were calculated. Eight studies met the inclusion criteria. The meta-analysis showed statistically significant differences in the complication rates (OR = 0.53; 95% CI = 0.34-0.84; p = 0.006) and incidence of catheter-related thrombosis (OR = 0.29; 95% CI = 0.11-0.76; p = 0.01) between midline catheter tip positioning in the subclavian vein and axillary vein. There were no significant differences in the catheter indwelling time or other complications such as phlebitis, catheter-related occlusion, catheter-related infiltration, pain, and catheter dislodgement between midline catheter tip positioning in the subclavian vein and axillary vein. There were statistically significant differences in the complication rates (OR = 0.23; 95% CI = 0.36-0.57; p < 0.001), incidence of catheter-related occlusion (OR = 0.29; 95% CI = 0.10-0.83; p = 0.02), and incidence of catheter-related infiltration (OR = 0.33; 95% CI = 0.17-0.63; p < 0.001) between midline catheter tip positioning in the proximal and distal axillary vein. Placement of the midline catheter tip in the subclavian vein was superior to that in the axillary vein in terms of complication rates and the incidence of catheter-related thrombosis. Whether different midline catheter tip locations lead to differences in the catheter indwelling time or the rates of other complications remains unclear. More high-quality studies incorporating relevant outcomes are needed for confirmation.

Prevalence of Work-Related Musculoskeletal Disorders among Nurses: A Meta-Analysis.

Background: Work-related musculoskeletal diseases (WMSDs) have a greater negative impact on nurses' physical and mental health. However, the epidemiologic characteristics of nurse WMSDs are unclear, and the reported prevalence of WMSDs varies widely. The aim of this meta-analysis was to provide a quantitative synthesis of WMSDs' prevalence in nurses and estimate the pooled prevalence of its. Methods: The PubMed, ScienceDirect, Web of Science, Cochrane Library, EMBASE, CINAHL, Ovid, WANFANG, VIP, China Knowledge Integrated, and CBM databases were searched for relevant studies. The retrieval period extended from database initiation to Mar 2022. After data extraction and quality assessment, a meta-analysis was performed using the Stata 16.0 software package. Results: Overall, 42 articles were included, yielding a total sample size of 36,934. The annual prevalence of WMSDs among nurses was found to be 77.2% (95% confidence interval: 0.725-0.819). The three anatomical areas with the highest prevalence of WMSDs among nurses were the lower back (at 59.5%), neck (at 53.0%) and shoulder (at 46.8%). Nurses in developed countries have a higher prevalence of WMSDs than those in developing countries. Conclusion: There was currently moderate evidence to suggest a high prevalence of WMSDs in nurses. National policies should aim to reduce their prevalence in this population.

Efficient estimation of pathwise differentiable target parameters with the undersmoothed highly adaptive lasso.

We consider estimation of a functional parameter of a realistically modeled data distribution based on observing independent and identically distributed observations. The highly adaptive lasso estimator of the functional parameter is defined as the minimizer of the empirical risk over a class of cadlag functions with finite sectional variation norm, where the functional parameter is parametrized in terms of such a class of functions. In this article we establish that this HAL estimator yields an asymptotically efficient estimator of any smooth feature of the functional parameter under a global undersmoothing condition. It is formally shown that the L 1-restriction in HAL does not obstruct it from solving the score equations along paths that do not enforce this condition. Therefore, from an asymptotic point of view, the only reason for undersmoothing is that the true target function might not be complex so that the HAL-fit leaves out key basis functions that are needed to span the desired efficient influence curve of the smooth target parameter. Nonetheless, in practice undersmoothing appears to be beneficial and a simple targeted method is proposed and practically verified to perform well. We demonstrate our general result HAL-estimator of a treatment-specific mean and of the integrated square density. We also present simulations for these two examples confirming the theory.

Predictors and outcomes of deep venous thrombosis in patients with acute ischemic stroke: results from the Chinese Stroke Center Alliance.

BACKGROUND: No large-scale, multicenter studies have explored the incidence rate and predictors of deep vein thrombosis (DVT) in patients with acute ischemic stroke (AIS). We aimed to determine the risk factors of DVT, and assess the association between DVT and clinical outcomes in AIS patients. METHODS: In total, 106,612 patients with AIS enrolled in the Chinese Stroke Center Alliance between August 2015 and July 2019 were included. The predictors of DVT in AIS patients were screened based on the logistic regression analysis for the comparison of the characteristics and clinical outcomes of patients with and without DVT. RESULTS: The overall incidence of DVT after AIS was 4.7%. Factors associated with increased incidence of DVT included advanced age, female sex, high admission National Institutes of Health Stroke Scale score, history of cerebral hemorrhage, transient ischemic attack (TIA), dyslipidemia, atrial fibrillation, and peripheral vascular disease, International Normalized Ratio (INR) <0.8 or >1.5, and blood uric acid >420 µmol/L. Ambulation and early antithrombotic therapy were associated with a lower incidence of DVT. Patients with DVT was associated with longer hospital stay (OR=1.44, 95% CI: 1.35-1.54), and higher in-hospital mortality (OR=1.68, 95% CI: 1.25-2.27). CONCLUSIONS: This large-scale, multi-center study showed that the occurrence of DVT in AIS patients is associated with various modifiable and objective indicators, such as abnormal INR and uric acid >420 µmol/L. Ambulatory status and early antithrombotic therapy can reduce the occurrence of DVT in AIS patients. In AIS patients, DVT may prolong the hospital stay and increase the risk of in-hospital mortality. Future research should focus on the clinical implementation of existing evidence on DVT prevention in AIS patients.

The roles of heteromorphic crystals and organic compounds in the formation of the submandibular stones.

Objective: The study aimed to analyze the formation process of submandibular stones based on the theory of biological mineralization and inorganic crystal structure variation. Study design: From January 2021 to December 2021, patients with submandibular stones treated in the Affiliated Hospital of Stomatology, Sun Yat-sen University (Guangzhou, China) were selected. According to the criterion of maximum transverse diameter ≥3 mm, a total of five submandibular stones meeting the requirement were included. After the surface of sample stones were washed, they were cut along the maximum transverse diameter. Next, the study employed Scanning Electron Microscope (SEM), Energy Dispersive X-ray Spectroscopy (EDS), and polycrystalline X-ray Diffraction (XRD) to analyze the composition and structure of submandibular stones. Results: Five submandibular stones were included. The organic and inorganic compounds showed a rhythmic or irregular distribution. Submandibular stones were highly occupied with carbon (C), oxygen (O), calcium (Ca), and phosphorus (P). Hydroxyapatite (HAP) was the primary inorganic component. In addition, the precursor of HAP, namely Amorphous Calcium Phosphate (ACP), was also found. Tetrahedral Substitution Index (TSI) and Ca/P ratio reflected the degree of structural variation in HAP crystal, which fluctuated from 5.62-90.71 and 1.10-1.35, respectively. Conclusions: The development of submandibular stones was influenced by inorganic crystals' chemical and structural variation as well as the organics' regulation towards the inorganic. The isomorphic substitution was accompanied by the occurrence of inorganic crystals, resulting in the crystal structure change. Organics might influence the appearance, aggregation, and mineralization of HAP during its formation.

Multiple benign fibrous histiocytomas of the mandible: A case report and review of the literature.

Benign fibrous histiocytoma (BFH) mostly occurs on the skin of the extremities, while it is unusual to manifest on the bone and mandibular involvement of BFH is even rarer. The present study reports a case of BFH in a 42-year-old female who had a slowly progressive swelling of the bilateral mandible and slight facial asymmetry over a period of 4 months. However, the outcome of this patient was unsatisfactory, with the first and second recurrence observed 16 and 46 months after surgery, respectively. The present case suggests that BFH has a risk of recurrence after transoral curettage. Regular follow-up is advised to detect tumor recurrence after the surgery of transoral curettage.

Nomogram to predict the risk of endoscopic removal failure with forceps/baskets for treating submandibular stones.

BACKGROUND: Endoscopic removal with forceps/baskets is favored in treating submandibular stones due to its minimal invasiveness. However, recent studies have found that endoscopic removal failure (ERF) is not unusual, and stones in such cases still need to be removed with other surgical methods. If the risk of ERF can be predicted preoperatively, it could be helpful for surgeons when choosing the appropriate therapy. AIM: To develop a predictive nomogram for the risk of ERF when treating submandibular stones based on their preoperative clinical features. METHODS: A total of 180 patients with 211 submandibular stones treated from January 2012 to December 2020 were included in the current study. Based on the preoperative clinical features of the stones, independent risk factors for ERF were identified by logistic regression analysis. The stones were then randomly divided into training and testing sets. A nomogram was constructed to predict the risk of ERF using the training set and then validated using both sets. The predictive performance of the nomogram was assessed by calibration curves and the concordance index (C-index). RESULTS: Three independent predictors, location (P = 0.040), transverse diameter (P < 0.001) and longitudinal diameter (P < 0.001) measured on the cone beam computed tomography (CBCT) images of the submandibular stones, were identified and included in the predictive nomogram. Calibration curves of the nomogram showed good agreement between the predicted and observed probabilities in both sets. The C-index in the training set was 0.917 (95%CI, 0.875-0.959) and that in the testing set was 0.925 (95%CI, 0.862-0.989). CONCLUSION: A nomogram based on the location, transverse and longitudinal diameters on CBCT images of submandibular stones showed satisfactory efficacy in predicting the risk of ERF preoperatively when treating submandibular stones.

Factors Influencing the Physical Restraint of Patients in the Neurosurgical Intensive Care Unit.

The purpose of this study was to investigate the current status of physical restraint of patients in the neurosurgical intensive care unit (NSICU) and analyze the factors influencing this measure using a cross-sectional study design. A total of 312 patients from four tertiary hospitals in NSICU were investigated in Beijing, China. The rate of physical restraint of patients in the NSICU was 42.9%. In 41.8% of cases, nurses performed physical restraint based on experience, and 45.5% of patients had physical restraint-related nursing records. Binary logistic regression analyses revealed that physical restraint was associated with delirium, mild-to-moderate disturbance of consciousness, history of extubation, surgery, and use of sedatives within 24 hour. Analysis of related factors can provide a reference for nurses and managers to improve physical restraint strategies.

Risk factors and nomogram for predicting carotid blowout syndrome based on computed tomography angiography.

OBJECTIVES: To identify independent factors for head and neck cancer (HNC) patients with carotid blowout syndrome (CBS) and construct a nomogram to predict risk of CBS preoperatively based on computed tomography angiography (CTA) imaging. SUBJECT AND METHODS: From January 2010 to July 2020, 73 HNC patients who had surgery in hospitalization and underwent CTA examination for head and neck region were included in this study. Vascular alterations and the relationship between carotid artery (CA) and tumor were evaluated in CTA. Clinical and CTA imaging features were distinguished by logistic regression analysis and used to perform receiver operating curve analysis. Nomogram was created to predict risk of CBS and assessed by concordance index (C-index) and calibration curve. RESULTS: Three independent risk factors were identified, including radical neck dissection, CA surrounded by tumor, and CA invaded by tumor without clear boundary. Area under curve of the combination of 3 variables was 0.836 (95% CI, 0.72-0.952, p < 0.001). The C-index of nomogram was 0.84 (95% CI, 0.73-0.94), and the calibration plot showed a good fitting between prediction and observation. CONCLUSIONS: We established a useful nomogram based on CTA imaging, which showed a satisfied efficacy for evaluating risk of CBS in HNC patients preoperatively.

Short-term exposure to ambient air pollution and atrial fibrillation hospitalization: A time-series study in Yancheng, China.

Atrial fibrillation (AF) is an important cardiovascular disease that causes a great burden of disease. However, there is limited evidence of a link between air pollution exposure and AF. This study aimed to explore the short-term association between air pollution and AF. We obtained daily hospitalization of AF in two major hospitals of Yancheng, China from May, 2015 to May, 2020. Generalized additive models with quasi-Poisson regression were used to assess the associations between six criteria air pollutants and AF hospitalization. We explored the lag patterns, and visualized the concentration-response relationships. The robustness of the association was tested by two-pollutant model, and we explored potential effect modification by age, sex and season. A total of 15,171 inpatients from two hospitals were collected in this study with an average daily count of eight patients. We observed consistent and significant associations between six air pollutants and AF on lag 0-4 days. A 10 ug/m3 increase in PM2.5 was associated with 2.81% (95%CI: 1.44%, 4.20%) changes in AF, and the effect estimate was 1.67% (95%CI: 0.77%, 2.59%) for PM10, 4.90% (95%CI: 1.69%, 8.22%) for NO2, 6.81% (95%CI: 0.46%, 13.57%) for SO2, 1.82% (95%CI: 0.60%, 3.06%) for O3; a 0.1 mg/m3 increase in CO was associated with 2.55% (95%CI: 0.91%, 4.21%) increments in AF. Associations of PM2.5 and PM10 were robust after adjusting for SO2, NO2, CO, and O3, but not vice versa. Female patients and those aged less 70 years had larger risk of AF associated with air pollution exposure. The concentration-response curves of the six pollutants were almost linear and increasing with no obvious thresholds. This time-series study in Yancheng demonstrated increased risk of AF and a delayed effect over lag 0-4 days. Our findings suggested need of prevention and protection against these environmental risk factors for AF in health departments.

Primary clinical study of radiomics for diagnosing simple bone cyst of the jaw.

OBJECTIVE: To screen the radiomic features of simple bone cysts of the jaws and explore the potential application of radiomics in pre-operative diagnosis of jaw simple bone cysts. METHODS: The investigators designed and implemented a case-control study. 19 patients with simple bone cysts who were admitted to the Department of Maxillofacial Surgery, Sun Yat-sen University Affiliated Stomatology Hospital from 2013 to 2019 were included in this study. Their clinical data and cone-beam computed tomography (CBCT) images were examined. The control group consisted of patients with odontogenic keratocyst. CBCT imaging features were analyzed and compared between the patient and control groups. RESULTS: Overall, 10,323 image features were extracted through feature analysis. A subset of 25 radiomic features obtained after feature selection were analyzed further. These 25 features were significantly different between the 2 groups (p < 0.05). The absolute value of correlation coefficient was 0.487-0.775. Gray-level co-occurrence matrix (GLCM) contrast, neighborhood gray tone difference matrix (NGTDM) contrast, and GLCM variance were the features with the highest correlation coefficients. CONCLUSIONS: Pre-operative radiomics analysis showed the differences between simple bone cysts and odontogenic keratocysts, can help to diagnose simple bone cysts. Three specific texture features-GLCM contrast, NGTDM contrast, and GLCM variance-may be the characteristic imaging features of simple bone cysts of the jaw.

Meta-analysis and systematic review of acupotomy combined with puncture and moxibustion in the treatment of knee osteoarthritis.

BACKGROUND: This study aimed to systematically evaluate the therapeutic effects of acupotomy combined with acupuncture and moxibustion on knee osteoarthritis (KOA), which was expected to provide a reference for clinical treatment of KOA using traditional Chinese medicine (TCM). METHODS: The databases PubMed, Embase, Medline, Ovid, and Springer were searched to retrieve randomized controlled trials (RCTs) on KOA treatment by acupotomy combined with acupuncture and moxibustion. The search time was set as from the date the database was established to 31 December 2020. The Cochrane Handbook for Systematic Reviews of Intervention 5.0.2 was used to conduct bias risk assessment on the included literature, and Review Manager 5.3 software was used for meta-analysis. RESULTS: A total of 10 RCTs were included in this study, including 1,073 participants. Meta-analysis results showed that compared with the control group, the clinical treatment efficiency of the experimental group was higher [mean difference (MD) =5.72; 95% confidence interval (CI): 3.39 to 9.64; Z=6.54; P<0.00001], and the postoperative visual analogue scale (VAS) scores were reduced (MD =-1.72; 95% CI: -2.41 to -1.03; Z=4.86; P<0.00001). DISCUSSION: Acupotomy combined with acupuncture and moxibustion treatment for KOA can increase clinical treatment efficiency, and relieve postoperative pain, suggesting that the combination of acupotomy, acupuncture, and moxibustion has better therapeutic effects on KOA and can be promoted clinically.

Development and Validation of a Prognostic Nomogram for Postoperative Recurrence-Free Survival of Ameloblastoma.

PURPOSE: Ameloblastoma is a benign odontogenic neoplasm with a high local recurrence rate if the operation is not thorough. However, a useful clinical tool for the quantitative assessment of the prognosis and risk of postoperative recurrence of ameloblastoma has not yet been constructed. This study aims to develop a prognostic nomogram model for ameloblastoma of the jaw to assist surgeons in surgical decision-making. PATIENTS AND METHODS: Patients who underwent initial surgery for ameloblastoma in our department from October 2004 to March 2020 were enrolled and randomly divided into training and validation sets. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify the independent prognostic factors, from which a nomogram for predicting 3-, 5- and 10-year recurrence-free survival (RFS) of ameloblastoma was constructed using the training set and internally validated using the validation set. The model performance was assessed by Harrell's concordance index (C-index) and calibration curves. RESULTS: A total of 302 eligible patients with ameloblastoma were enrolled, 54 of whom were confirmed to relapse during the follow-up period of 6 to 191 months. Four independent predictors, including cortical bone perforation, root(s) resorption, WHO classification, and treatment pattern, were identified and included in the construction of a nomogram for recurrence-free survival (RFS), which showed promising calibration performance and discrimination in the training set (C-index 0.790, 95% confidence interval [CI] 0.735-0.845) and the validation set (C-index 0.734, 95% CI 0.599-0.869). CONCLUSION: A favorable nomogram was developed that accurately predicted the RFS of patients with ameloblastoma based on individual characteristics. Risk stratification using the nomogram could optimize tailored therapy and follow-up.

FOSL1 promotes metastasis of head and neck squamous cell carcinoma through super-enhancer-driven transcription program.

Previously, we discovered that FOSL1 facilitates the metastasis of head and neck squamous cell carcinoma (HNSCC) cancer stem cells in a spontaneous mouse model. However, the molecular mechanisms remained unclear. Here, we demonstrated that FOSL1 serves as the dominant activating protein 1 (AP1) family member and is significantly upregulated in HNSCC tumor tissues and correlated with metastasis of HNSCC. Mechanistically, FOSL1 exerts its function in promoting tumorigenicity and metastasis predominantly via selective association with Mediators to establish super-enhancers (SEs) at a cohort of cancer stemness and pro-metastatic genes, such as SNAI2 and FOSL1 itself. Depletion of FOSL1 led to disruption of SEs and expression inhibition of these key oncogenes, which resulted in the suppression of tumor initiation and metastasis. We also revealed that the abundance of FOSL1 is positively associated with the abundance of SNAI2 in HNSCC and the high expression levels of FOSL1 and SNAI2 are associated with short overall disease-free survival. Finally, the administration of the FOSL1 inhibitor SR11302 significantly suppressed tumor growth and lymph node metastasis of HNSCC in a patient-derived xenograft model. These findings indicate that FOSL1 is a master regulator that promotes the metastasis of HNSCC through a SE-driven transcription program that may represent an attractive target for therapeutic interventions.

Nonparametric bootstrap inference for the targeted highly adaptive least absolute shrinkage and selection operator (LASSO) estimator.

The Highly-Adaptive least absolute shrinkage and selection operator (LASSO) Targeted Minimum Loss Estimator (HAL-TMLE) is an efficient plug-in estimator of a pathwise differentiable parameter in a statistical model that at minimal (and possibly only) assumes that the sectional variation norm of the true nuisance functions (i.e., relevant part of data distribution) are finite. It relies on an initial estimator (HAL-MLE) of the nuisance functions by minimizing the empirical risk over the parameter space under the constraint that the sectional variation norm of the candidate functions are bounded by a constant, where this constant can be selected with cross-validation. In this article we establish that the nonparametric bootstrap for the HAL-TMLE, fixing the value of the sectional variation norm at a value larger or equal than the cross-validation selector, provides a consistent method for estimating the normal limit distribution of the HAL-TMLE. In order to optimize the finite sample coverage of the nonparametric bootstrap confidence intervals, we propose a selection method for this sectional variation norm that is based on running the nonparametric bootstrap for all values of the sectional variation norm larger than the one selected by cross-validation, and subsequently determining a value at which the width of the resulting confidence intervals reaches a plateau. We demonstrate our method for 1) nonparametric estimation of the average treatment effect when observing a covariate vector, binary treatment, and outcome, and for 2) nonparametric estimation of the integral of the square of the multivariate density of the data distribution. In addition, we also present simulation results for these two examples demonstrating the excellent finite sample coverage of bootstrap-based confidence intervals.

One-step targeted maximum likelihood estimation for time-to-event outcomes.

Researchers in observational survival analysis are interested in not only estimating survival curve nonparametrically but also having statistical inference for the parameter. We consider right-censored failure time data where we observe n independent and identically distributed observations of a vector random variable consisting of baseline covariates, a binary treatment at baseline, a survival time subject to right censoring, and the censoring indicator. We assume the baseline covariates are allowed to affect the treatment and censoring so that an estimator that ignores covariate information would be inconsistent. The goal is to use these data to estimate the counterfactual average survival curve of the population if all subjects are assigned the same treatment at baseline. Existing observational survival analysis methods do not result in monotone survival curve estimators, which is undesirable and may lose efficiency by not constraining the shape of the estimator using the prior knowledge of the estimand. In this paper, we present a one-step Targeted Maximum Likelihood Estimator (TMLE) for estimating the counterfactual average survival curve. We show that this new TMLE can be executed via recursion in small local updates. We demonstrate the finite sample performance of this one-step TMLE in simulations and an application to a monoclonal gammopathy data.

Differences between epithelial and mesenchymal human tongue cancer cell lines in experimental metastasis.

Distant metastasis represents the outcome with the worst prognosis for various types of malignant tumors, but little is known regarding the impact of interacting epithelial and mesenchymal phenotypic cancer cells within its etiopathogenesis. In a novel animal model, 48 male athymic Balb/c nude mice underwent subcutaneous and intravenous injection of human tongue cancer cell lines of green fluorescent mesenchymal and red fluorescent epithelial phenotypes, in order to visualize and monitor eventual phenotypic interaction in lung metastasis as well as experimental metastasis in in vivo, ex vivo and histopathological analyses. While the epithelial, but not the mesenchymal, phenotypic human tongue cancer cell line led to direct metastasis in the lungs when injected intravenously, neither of them, even when injected in combination, were able to establish distant metastasis. The results of the present study provide evidence regarding the role of epithelial phenotypic cancer cells in the release of experimental metastasis following tail vein injection in male athymic Balb/c nude mice, in addition to proving fluorescent human tongue cancer cells may be reliably detected under a fluorescence microscope even 8 weeks after the two injection types.